Tissue characterization based on impedance images and on impedance measurements

ABSTRACT

Apparatus for aiding in the identification of tissue type for an anomalous tissue in an impedance image comprising a first device providing a polychromic immitance map of a portion of the body; a second devise determining a plurality of polychromic measures from one or both of a portion of the body; and a display which displays an indication based on the plurality of polychromic measures.

CROSS REFERENCE TO RELATED APPLICATION

This application is a Divisional of U.S. patent application Ser. No.09/995,217, filed Mar. 5, 2002, now U.S. Pat. No. 6,678,552, which is acontinuation of U.S. patent application Ser. No. 09/928,678, filed Aug.13, 2001, now U.S. Pat. No. 6,421,559, which is a continuation of U.S.patent application Ser. No. 09/537,004, filed Mar. 28, 2000, now U.S.Pat. No. 6,308,097, which is a continuation of U.S. patent applicationSer. No. 09/150,224, filed Sep. 9, 1998, now U.S. Pat. No. 6,055,452which is a continuation of U.S. application Ser. No. 08/725,927, filedOct. 4, 1996, now U.S. Pat. No. 5,810,742 which is aContinuation-in-part of International Application No. PCT/US95/06141,filed May 19, 1995, the disclosure of which is incorporated by referencein its entirety.

FIELD OF THE INVENTION

The present invention relates to systems for tissue characterizationbased on impedance measurement at a point or at an array of points.

BACKGROUND OF THE INVENTION

The measurement of electrical potentials on the skin has many uses. Forexample, electrocardiograms are derived from measuring the potentialgenerated by the heart of a patient at various points on the skin.

Skin potentials are also measured in apparatus for determining theelectrical impedance of human tissue, including two-dimensional (e.g.,U.S. Pat. Nos. 5,063,937, 4,291,708 and 4,458,694) or three-dimensional(e.g., U.S. Pat. Nos. 4,617,939 and 4,539,640) mapping of the tissueimpedance of the body In such systems an electrical potential isintroduced at a point or points on the body and measured at other pointsat the body. Based on these measurements and on algorithms which havebeen developed over the past several decades, an impedance map or otherindication of variations in impedance can be generated.

U.S. Pat. Nos. 4,291,708 and 4,458,694 and “Breast Cancer screening byimpedance measurements” by G. Piperno et al. Frontiers Med. Biol. Eng.,Vol. 2, pp 111–117, the disclosures of which are incorporated herein byreference, describe systems in which the impedance between a point onthe surface of the skin and some reference point on the body of apatient is determined. These references describe the use of amulti-element probe for the detection of cancer, especially breastcancer, utilizing detected variations of impedance in the breast.

In these references a multi-element probe is described in which a seriesof flat., stainless steel, sensing elements are mounted onto a PVC base.A lead wire is connected between each of these elements and detectorcircuitry. Based on the impedance measured between the elements and aremote part of the body, signal processing circuitry determines theimpedance variations in the breast. Based on the impedancedetermination, tumors, and specially malignant tumors, can be detected.

The multi-element probe is a critical component in this system and inother systems which use such probes. On one hand the individual elementsmust make good contact with the skin and with the corresponding pointson the sensing or processing electronics while also being well isolatedfrom each other. On the other hand, use of gels to improve skin contactcarries the risk of cross-talk, dried gel build-up on the elements andinter-patient hygienic concerns.

A paper titled “Capacitive Sensors for In-Vivo Measurements of theDielectric Properties of Biological materials” by Karunayake P. A. P.Esselle and Stanislaw S. Stuchly (IEEE Trans. Inst & Meas. Vol. 37, No.1, p. 101–105) describes a single element probe for the measurement ofin vivo and in vitro measurements of the dielectric properties ofbiological substances at radio and microwave frequencies. The sensorwhich is described is not suitable for impedance imaging.

A paper entitled “Messung der elektrischen Impedance vonorganen—Apparative Ausuüstung für Forschung und klinishe Anwendung” byE. Gersing (Biomed. Technik 36 (1991), 6–11) describes a system whichuses single element impedance probes for the measurement of theimpedance of an organ. The device described is not suitable forimpedance imaging.

A Paper titled “MESURE DE L'IMPEDANCE DES TISSUS HEPATIQUELESTRANSFORMES PAS DES PROCESSUS LESIONELS” by J. Vrana et al. (Ann.Gastroentreol. Hepetol., 1992, 28, no. 4, 165–168) describes a probe forassessing deep tissue by use of a thin injection electrode. Theelectrode was positioned by ultrasound and specimens were taken forcytological and histological assessment. The electrode was constitutedon a biopsy needle used to take the samples.

A paper titled “Continuous impedance monitoring during CT-guidedstereotactic surgery: relative value in cystic and solid lesions” by V.Rajshekhar (British Journal of Neurosurgery (1992) 6, 439–444) describesusing an impedance probe having a single electrode to measure theimpedance characteristics of lesions. The objective of the study was touse the measurements made in the lesions to determine the extent of thelesions and to localize the lesions more accurately. The probe is guidedto the tumor by CT and four measurements were made within the lesion asthe probe passed through the lesion. A biopsy of the lesion wasperformed using the outer sheath of the probe as a guide to position,after the probe itself was withdrawn.

A paper titled “Rigid and Flexible Thin-Film Multi-electrode Arrays forTransmural Cardiac Recording” by J. J. Mastrototaro et al. (IEEE TRANS.BIOMED. ENG. Vol. 39, No. 3, March 1992, 271–279) describes a needleprobe and a flat probe each having a plurality of electrodes for themeasurement of electrical signals generated in the heart.

A paper entitled “Image-Based Display of Activation Patterns Derivedfrom Scattered Electrodes” by D. S. Buckles et al. (IEEE TRANS. BIOMEDENGR. Vol. 42, No. 1, January 1995, 111–115) describes a system formeasurement of electrical signals generated on the heart by use of anarray of electrodes on a substrate. The heart with the electrodes inplace is viewed by a TV camera and an operator marks the positions ofthe electrodes on a display. The system then displays the heart (asvisualized prior to the placement of the electrodes) with the positionmarkings.

A paper entitled “Development of a Multiple Thin-Film Semimicro DC-Probefor Intracerebral Recordings” by G. A. Urban et al. (IEEE TRANS. BIOMEDENGR. Vol. 37, No. 10, October 1990, 913–917) describes an elongatealumina ceramic probe having a series of electrodes along its length andcircumference for measuring functional parameters (electrical signals)in the brain. Electrophysiological recording, together withelectrostimulation at the target point during stereotactic surgery, wasperformed in order to ensure exact positioning of the probe afterstereotactic calculation of the target point. Bidimensional X-Rayimaging was used in order to verify the exact positioning of theelectrode tip.

SUMMARY OF THE INVENTION

It is an object of certain aspects of the invention to provide amulti-element probe having improved and more uniform and repeatablecontact with the skin with minimal operator expertise and minimal riskof cross-patient contamination.

It is an object of certain aspects of the invention to provide improvedinter-element electrical isolation, and to permit sliding of the probewhile it is urged against the skin.

It is an object of certain aspects of the invention to provide arelatively inexpensive disposable multi-element probe.

It is an object of certain aspects of the invention to provide amulti-element probe having sufficient transparency to allow for viewingof tissue surface features and to allow for referencing the probe withrespect to physical features of or on the skin.

It is an object of certain aspects of the invention to provide a methodof distinguishing between artifacts and abnormalities.

It is an object of certain aspects of the invention to provide a systemfor electrical impedance imaging which simultaneously acquires, uses andpreferably displays both capacitance and conductance information.

It is an object of certain aspects of the invention to provide a systemfor electrical impedance testing of the breast or other body regionwhich provides more accurate information regarding the position ofimpedance abnormalities detected in the breast or other region.

It is an object of certain aspects of the invention to provide forelectrical impedance testing with a variable spatial resolution.

It is an object of certain aspects of the invention to provide for twodimensional electrical impedance testing giving an indication of thedistance of an abnormality from the surface of the skin.

It is an object of certain aspects of the invention to provide apparatusespecially suitable for breast impedance measurements.

It is an object of certain aspects of the invention to provide guidancefor placement of elongate objects such as biopsy needles, localizationneedles, fiber optic endoscopes and the like using real time and/orrecorded stereotactic images to guide the object.

It is a further object of certain aspects of the invention to provide abiopsy needle having an impedance measuring function to aid in thetaking of a biopsy.

It is an object of certain aspects of the invention to provide moredirect comparison between the results of electrical impedance maps andthe results of optical, ultrasound or other imaging modalities.

It is an object of certain aspects of the invention to provide apparatusand method for indicating, on an anatomical illustration, the locationand region from which an impedance image, shown together with theillustration is derived.

It is an object of certain aspects of the invention to provide apparatuswhich facilitates direct comparison between X-Ray and impedancemammographic images, as for example by superposition of the images.

It is an object of certain aspects of the invention to provide a methodof determining a polychromic (multi-frequency) impedance map.

It is an object of certain aspects of the invention to optimize theimpedance mapping utilizing a pulsed voltage excitation.

It is an object of certain aspects of the invention to provide palpationand tactile sensing of an area while simultaneously providing animpedance image of the area.

It is an object of certain aspects of the invention to allow for theidentification of tissue types from impedance maps.

In general, the term “skin” as used herein means the skin or othertissue of a subject.

The present inventor has found that when, in an impedance image, ananomaly is perceived, the type of tissue underlying the position of theanomaly on the image may generally be determined by a characterizationprocedure which includes the determination of a number of polychromicmeasures for the anomaly and surrounding non-anomalous tissue andcomparison of the measures with ranges of values of individualpolychromic measures or their combinations which are characteristic ofvarious types of tissue. It has been found that normal tissue such asbreast tissue, nipples and the infra-mammary ridge, ribs andCosto-chondral Junctions and benign hyperplasia can generally bedistinguished from cancerous tumors and precancerous a typicalhyperplasia. These measures are based on the structure and form of thedeviation of the capacitance and conductance of the anomalous portion ofthe image from that of the surrounding, normal tissue. For those caseswhere there is some ambiguity between some types of tissue, knowledge ofthe anatomy of the imaged area or palpation of the area can often removethe ambiguity or additional views can be taken to remove the ambiguity.

In an image the measures are preferably determined by comparing thecapacitance or conductance of the anomalous pixels on the image to becharacterized with the capacitance or conductance of normative tissuearound the mean or median value of the capacitance or conductance,typically in terms of quantified deviation of a given pixel or regionfrom the median in the image, as measured in multiples of the estimatedstandard deviation or coefficient of variance.

The method is also potentially useful to determine tissue types insituations where either a single impedance probe is used or where theimage is small and only anomalous areas are imaged. In these cases thecomparison is made between the values of capacitance or conductancemeasured for the anomalous region as compared to the capacitance orconductance measured for a nearby region known to be normal.

As used herein the term immitance means either the complex admittance orimpedance. Furthermore the term polychromic measure is a measure whichis based on the immitance or on the real or imaginary part thereof or ona combination of the immitance and/or the real part thereof and/or theimaginary part thereof at a plurality of frequencies, i.e., on thespectrum thereof.

There is therefore provided, in accordance with a preferred embodimentof the invention apparatus for aiding in the identification of tissuetype for an anomalous tissue in an impedance image comprising:

means for providing an polychromic immitance map of a portion of thebody;

means for determining a plurality of polychromic measures, preferablynormalized measures, of an anomalous region of the immitance image; and

a display which displays an indication based on said plurality ofpolychromic measures.

Preferably the apparatus includes means for providing a map of saidpolychromic measures and wherein said indication includes a display of aplurality of said maps.

In a preferred embodiment of the invention the display includes anoverlay of maps of said polychromic measures.

Preferably the apparatus includes means for matching the values of theplurality of measures with predetermined values of the measures toidentify the tissue type of the anomalous tissue.

In one preferred embodiment of the invention the indication is thedisplay of a map of said determined tissue type.

There is further provided, in accordance with a preferred embodiment ofthe invention, apparatus for determining a tissue type for an anomaloustissue comprising:

means for determining a plurality of polychromic measures of theanomalous tissue; and

means for matching the values of the plurality of measures withpredetermined values of the measures to identify the tissue type of theanomalous tissue.

There is further provided, in accordance with a preferred embodiment ofthe invention, a method of determining a tissue type for tissue in ananomalous region in an immitance image, comprising:

determining a plurality of polychromic measures, preferably normalizedmeasures, of said anomalous region; and

matching the values of the plurality of measures to identify the tissuetype of the anomalous region.

There is further provided, in accordance with a preferred embodiment ofthe invention, a method of determining a tissue type for an anomaloustissue:

determining a plurality of polychromic measures, preferably normalizedmeasures, of the anomalous tissue;

matching the values of the plurality of measures with predeterminedvalues to identify the tissue type of the anomalous tissue.

Preferably, one of the polychromic measures is derived from the sum,over a plurality of frequencies, of the positive deviations of thecapacitance of the anomaly from that of typical nonanomolous regions.

Preferably, one of the polychromic measures is derived from the sum,over a plurality of frequencies, of the negative deviations of thecapacitance of the anomaly from that of typical nonanomolous regions.

Preferably, one of the polychromic measures is derived from the sum,over a plurality of frequencies, of the positive deviations of theconductance of the anomaly from that of typical nonanomolous regions.

Preferably one of the measures is the integral of the phase or the sumof phase values over a range of frequencies.

Preferably, one of the measures is the difference between the integralof the difference between the phase at a point and the mean or medianvalue of the phase in the image, over a range of frequencies.

Preferably, one of the measures is the derivative of the capacitancecurve or its logarithm as a function of frequency, evaluated at a givenfrequency.

Preferably, one of the measures is the derivative of the conductancecurve or its logarithm as a function of frequency, evaluated at a givenfrequency.

Preferably, one of the measures is a frequency at which the phase of theimpedance reaches a specified value, preferably 45 degrees.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be more fully understood and appreciated from thefollowing detailed description, taken in conjunction with the drawingsin which:

FIG. 1 is an overall view of an imp dance mapping system especiallysuitable for breast impedance mapping in accordance with a preferredembodiment of the invention;

FIG. 2 is a perspective view of an imaging head suitable for breastimpedance mapping in accordance with a preferred embodiment of theinvention;

FIGS. 3A and 3B show partially expanded views of two preferred probehead configurations suitable for use in the imaging head of FIG. 2;

FIG. 4 is a top view of a portion of a multi-element probe in accordancewith a preferred embodiment of the invention;

FIG. 5A is a partial, partially expanded cross-sectional side view ofthe probe of FIG. 4 along lines V—V, suitable for the probe headconfiguration of FIG. 3B;

FIG. 5B is a partially expanded cross-sectional side view of analternative probe in accordance with a preferred embodiment of theinvention;

FIG. 5C shows an alternative embodiment of a multi-element probe, inaccordance with a preferred embodiment of the invention;

FIG. 6A is a perspective view of a hand held probe in accordance with apreferred embodiment of the invention;

FIG. 6B shows a partially expanded bottom view of the probe of FIG. 6A,in accordance with a preferred embodiment of the invention;

FIG. 7A is a perspective view of a fingertip probe in accordance with apreferred embodiment of the invention;

FIG. 7B shows a conformal multi-element probe;

FIG. 8 shows an intra-operative probe used determining the position ofan abnormality in accordance with a preferred embodiment of theinvention;

FIG. 9 shows a laparoscopic probe in accordance with a preferredembodiment of the invention;

FIG. 10 shows a biopsy needle in accordance with a preferred embodimentof the invention;

FIG. 11A illustrates a method of using the biopsy needle of FIG. 10, inaccordance with a preferred embodiment of the invention;

FIG. 11B illustrates a portion of a display used in conjunction with themethod of FIG. 11A;

FIG. 11C shows a biopsy guiding system in accordance with a preferredembodiment of the invention:

FIG. 11D shows a frontal biopsy guiding system in accordance with apreferred embodiment of the invention;

FIG. 11E shows a lateral biopsy guiding system in accordance with apreferred embodiment of the invention;

FIG. 12 shows, very schematically, the inter-operative probe of FIG. 8combined with a video camera use to more effectively correlate animpedance measurement with placement of the probe.

FIG. 13 illustrates a laparoscopic probe according to the invention usedin conjunction with a fiber-optic illuminator-imager;

FIG. 14 illustrates a display, according to a preferred embodiment ofthe invention showing both capacitive and conductance imagesillustrative of a typical hyperplasia;

FIG. 15 illustrates a display, according to a preferred embodiment ofthe invention showing both capacitive and conductance imagesillustrative of a carcinoma;

FIG. 16 illustrates a method useful for verifying a detected localimpedance deviation as being non-artifactal and for estimating thedeviation;

FIGS. 17A and 17B are a block diagram of circuitry suitable forimpedance mapping in accordance with a preferred embodiment of theinvention; and

FIGS. 18A–18C show maps of polychromic measures characteristic ofcertain tissue types.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Reference is made to FIGS. 1 and 2 which illustrate an impedance mappingdevice 10 suitable for mapping the impedance of a breast.

Mapping device 10 includes an imaging head 12, which is described below,which holds the breast and provides contact therewith for providingelectrical excitation signals thereto and for receiving resultantelectrical signals therefrom. Signals to and from the head are generatedand received by a computer/controller 14 which produces impedance mapsof the breast under test for display on a monitor 16. The impedance mapsmay be stored in computer/controller 14 for later viewing or processingor hard copies may be provided by a hard copy device 18 which may be alaser printer, video printer, Polaroid or film imager or multi-imager.

The entire mapping device 10 may be conveniently mounted on a dolly 20to facilitate placement of the imaging head with respect to the patient.

FIG. 1 also shows a hand held probe 100, described in more detail below,and a reference probe 13.

FIG. 2 shows imaging head 12 in more detail. Head 12 comprises a movablelower plate probe 22 and a stationary upper plate probe 24 which ismounted on a pair of rails 26 to allow the distance between plate probes22 and 24 to be varied.

Movement of plate probe 22 along rails 26 may be achieved either by amotor (not shown) including suitable protection against over-pressure asis traditional in X-ray breast imaging, or by hand.

Either or both of plate probes 22 and 24 are provided with multi-elementprobes 28 and 30 respectively, which are described more fully below,which electrically contact the breast with a plurality of sensingelements to optionally provide electrical excitation to the breast andto measure signals generated in response to the provided signals.Alternatively, electrical excitation to the breast is provided byreference probe 13 which is placed on the arm, shoulder or back of thepatient, or other portion of the patient.

In practice, a breast is inserted between probes 28 and 30 and plateprobe 24 is lowered to compress the breast between the probes. Thiscompression reduces the distance between the probes and provides bettercontact between the sensing elements and the skin of the breast.Although compression of the breast is desirable, the degree ofcompression required for impedance imaging is much lower than for X-Raymammography, and the mapping technique of the present invention istypically not painful.

Alternatively or additionally, the probes are curved to conform with thesurface of the breast.

Head 12 is provided with a a pivot (not shown) to allow for arbitraryrotation of the head about one or more of its axes. This allows for bothmedio-lateral and cranio-caudal maps of the breast to be acquired, atany angular orientation about the breast. Preferably, head 12 may betilted so that the surfaces of plate probes 22 and 24 are oriented witha substantial vertical component so that gravity assists the entry ofthe breast into the space between the maximum extent and to keep it frominadvertently falling out. This is especially useful when the patientleans over the plates so that her breasts are positioned downwardlybetween the plate probes.

Furthermore, in a preferred embodiment of the invention, one or both ofprobes 28 and 30 may be rotated about an axis at one end thereof, by arotation mechanism 27 on their associated plate probes 22 or 24, such asis shown in FIG. 2 for probe 28. Additionally or alternatively, probes28 and/or 30 may be slidable, as for example along members 31.

Such additional sliding and rotating flexibility is useful for providingmore intimate skin contact of the probes with the breast, which has agenerally conical shape. Furthermore, such flexibility allows for betterimaging of the areas of the breast near the chest wall or the rib cage,which are extremely difficult to image in x-ray mammography.

FIGS. 3A and 3B show partially expanded views of two probe headconfigurations suitable for use in the imaging head of FIG. 2, inaccordance with preferred embodiments of the invention.

In the embodiment of FIG. 3A, a preferably removable multi-element probe62, which is described below in more detail, is attached to a probe headbase 50 via a pair of mating multi-pin connectors 51 and 52. A cable 53couples connector 52 to computer 14. When multi-element probe 62 isinserted into base 50 (that is to say, when connector 51 is fullyinserted into connector 52), the relatively stiff bottom of probe 62rests on ledges 54 formed in the base, such that the surface 55 of thebase and the surface of element 62 are preferably substantiallycoplanar.

In the embodiment of FIG. 3B, a series of contacts 82 are formed on base50 and a disposable multi-element probe 62′ is attached to the contactsas described below with reference to FIGS. 5A and 5B. Cable 53 couplesthe contacts to computer 14.

FIGS. 4, 5A and 5B show top and side views of a portion of multi-elementprobe 62′ and contacts 74, while FIGS. 5A and 5B show a partiallyexpanded cross-sectional side view of probe 62′ along lines V—V. Whilethe embodiment shown in FIGS. 4, 5A and 5B is especially suitable forthe probe head configuration of FIG. 3B, much of the structure shown inthese FIG. 5 is common to multi-element probes used in otherconfigurations described herein.

As shown in FIGS. 4, 5A and 5B, disposable multi-element probe 62′preferably incorporates a plurality of sensing elements 64, separated byseparator or divider elements 66.

As shown more clearly in FIGS. 5A and 5B, sensing elements 64, comprisea bio-compatible conductive material (for example Neptrode E0751 orNeptrode E0962 Hydrogel distributed by Cambrex Hydrogels, Harriman,N.Y.) such as is sometimes used for ECG probes in a well 70 formed by afirst, front, side of a mylar or other flexible, non-conductingsubstrate 68, such as a thin mylar sheet and the divider elements 66. Asuitable thickness for the mylar sheet is approximately 0.2 mm for probe62′. The substrate is preferably pierced in the center of each well. Thehole resulting from the piercing is filled with a conducting materialwhich is also present on the bottom of well 70 and on a second, back,side of substrate 68 to form a pair of electrical contacts 72 and 74 oneither side of the substrate and an electrically conducting feed-through76 between the pair of contacts. As shown, a separate contact pair andfeed-through is provided for each sensing element.

Alternatively, the substrate may be formed of any suitable inertmaterial including plastics such as polyethylene, polypropylene, PVC,etc.

Wells 70 may be formed in a number of ways. One method of forming thewells is to punch an array of square holes in a sheet of plastic, suchas polypropylene, which is about 0.2–1 mm thick. This results in a sheetcontaining only the divider elements. This sheet is bonded to substrate68 which has been pre-pierced and in which the contacts andfeed-throughs have been formed. Another method of forming the wells isto emboss a substrate containing the contacts and feed-throughs to formdivider elements in the form of ridges which protrude from the substrateas shown in FIG. 5B. Yet another method of producing the wells is byprinting the well walls using latex based ink or other bio-compatiblematerial having a suitable firmness and flexibility. Another method ofproduction is by injection molding of the substrate together with thedivider elements. And yet another method of producing the wells is bylaminating to the substrate a preformed grid made by die cutting thearray of divider elements in a sheet of plastic, injection molding, orother means.

The conductors and feed-throughs may be of any conductive material whichwill provide reliable feed-through plating of the holes. One method ofmanufacturing the contacts and holes is by screen printing of thecontacts on both sides of the substrate. If conductive paste having asuitable viscosity is used, the paste will fill the hole and form areliable contact between contacts 72 and 74. Although many conductivematerials can be used, non-polarizing conductors, such as silver/silverchloride are preferred. A conductive paste suitable for silk screeningthe conductors onto the substrate is Pad Printable Electricallyconductive Ink No. 113-37 manufactured and sold by Creative MaterialsInc., Tyngsboro, Mass.

In general contacts 72 and 74 are only 10–200 microns thick and wells 70are generally filled with conductive viscous gel material or hydrogelmaterial to within about 0.2 mm of the top of the dividing elements. Ingeneral, if low separators are used, the hydrogel may be omitted.However, in the preferred embodiment of the invention, the wells are atleast partially filled by hydrogel or a similar material.

Hydrogel is available in both UV cured and heat cured compositions. Ineither case a measured amount of uncured semi-liquid hydrogel isintroduced into each well and the hydrogel is cured. Alternatively, thewells are filled with the uncured material and a squeegee which ispressed against the top of the divider elements with a predeterminedforce is moved across the top of the divider elements. This will resultin the desired gap between the top of the hydrogel and the top of thewells.

In an alternative embodiment of the invention, the hydrogel material isreplaced by a sponge material or similar supportive matrix impregnatedwith conductive viscous gel or the well is simply filled with theconductive gel to the desired height.

During use of the probe, the probe is urged against the skin which isforced into the wells and contacts the hydrogel or alternativeconductive material. Optionally, a somewhat viscous conductive gel, suchas Lectron II Conductivity Gel (Pharmaceutical Innovations, Inc. Newark,N.J.), may be used to improve contact with the skin. In this case, thedividing elements will reduce the conduction between the cells such thatthe substantial independence of the individual measurements ismaintained. Alternatively, the conductive gel may be packaged togetherwith the probe, with the conductive gel filling the space between thetop of the hydrogel and the top of the wells. The use of a conductivegel is preferred since this allows for sliding movement of the probe andits easy positioning while it is urged against the skin. The separatorssubstantially prevent the conductive gel from creating a low conductancepath between adjoining sensing elements and also keep the hydrogelelements from touching each other when the probe is applied to the skinwith some pressure.

In a further preferred embodiment of the invention, the sensing elementsare formed of a conductive foam or sponge material such as siliconerubber or other conductive rubber or other elastomer impregnated withsilver or other conductive material, as shown in FIG. 5C. FIG. 5C showsthe sensing elements without walls 66. Elements which protrude from thesubstrate as shown in FIG. 5C may achieve substantial electricalisolation from one another by spacing them far enough apart so that donot contact each other in use or by coating their lateral surfaces withinsulating material such as polyethylene or other soft non-conductiveplastic or rubber.

For relatively short rigid or compressible elements, it has been foundthat reducing the size of the sensing elements such that no more than70% (and preferably no more than 50%) of the area of the array iscovered is sufficient to reduce the “cross-talk” between adjoiningelements to an acceptable level.

If sufficiently good isolation is achieved between probe elements bytheir spacing alone, then foam or other elements without hydrogel andwithout walls 66 may be provided. Sensing elements such as those shownin FIG. 5C conform and mate to uneven surfaces when pressed againsttissue.

Multi-element probe 62′, which is preferably used for only one patientand then discarded, is preferably removably attached to a probe holderwhich preferably comprises a printed circuit board 80 having a pluralityof contacts 82 corresponding to the contacts 74 on the back of thesubstrate, each PC board contact 82 being electrically connected to acorresponding contact 74 on the substrate. To facilitate alignment ofthe matching contacts, an alignment guide 90 is preferably provided onor adjacent to PC board 80 (FIG. 4). This guide may consist of a seriesof guide marks or may consist of a raised edge forming a well into oronto which the substrate is inserted. Conductors within PC board 80connect each of the contacts to one of the pins of connector 51, whichis preferably mounted on PC board 80.

Alternatively and preferably, as described below with respect to FIG.6B, the guide may consist of two or more pins located on or near PCboard 80, which fit into matching holes in probe 62′.

Alternatively as shown in FIG. 58, the back side of the embossing ofsubstrate 68 is used as the guide for one or more protruding elements 83which are preferably mounted on PC board 80. Preferably a plurality ofprotruding elements are provided to give good alignment of the substratewith the PC board. The elements may run along the periphery of the probeand form a frame-like structure as shown in FIG. 5B or may run betweenthe elements or may take the form of x shaped protuberances which matchthe shape of the embossing at the corners of the wells.

Protruding elements 83 may be formed of polycarbonate, acetate, PVC orother common inert plastic, or of a noncorrosive metal such as stainlesssteel.

A wire 84 is connected to each PC contact 82 and is also connected toapparatus which provides voltages to and/or measures voltages and/orimpedances at the individual sensing elements 64, as described below.

In a preferred embodiment of the invention, conductive adhesive spots 86preferably printed onto the back of the substrate are used toelectrically and mechanically connect contacts 74 with their respectivecontacts 82. Preferably a conductive adhesive such as Pressure SensitiveConductive Adhesive Model 102-32 (Creative Materials Inc.) is used.Alternatively, the adhesive used for printing the contacts/feed-throughsis a conducting adhesive and adhesive spots 86 may be omitted.Alternatively, pins, which protrude from the surface of PC board 80 andare connected to wires 84 pierce the substrate (which may be pre-bored)and contact the gel or hydrogel in the wells. A pin extending from thesubstrate may also be inserted into a matching socket in the PC board toform the electrical connection between the sensing element and the PCboard. Alternatively, the entire back side of the substrate can be,adhered to the printed circuit board surface using an anisotropicallyconductive thin film adhesive which has a high conductivity betweencontacts 74 and 82 and which has a low conductivity resulting inpreferably many times higher resistance between adjoining contacts thanbetween matching contacts, in practice at least one hundred timesdifferent. An example of such adhesive is tape NO. 3707 by MMMCorporation, Minneapolis Minn. However, due to the difficulty ofapplying such material without trapped air bubbles, it may be preferablyto apply adhesive only to the contacts themselves. In practice a releaseliner of polyethylene, mylar or paper with a non-stick surface on oneside is provided on the lower side of the adhesive sheet. This linerprotects the adhesive layer prior to connection of the disposablemulti-element probe to the probe holder and is removed prior to theconnection of the probe to the holder.

Preferably, the impedance between contacts 82 and skin side of theconducting material in the wells should be less than 100 ohms at 1 kHzand less than 400 ohms at 10 Hz.

Impedance between any pair of contacts 82, with the multi-element probemounted should preferably be greater than 10 kohm at 1 kHz or 100 kohmat 10 Hz.

Another suitable material for producing substrates is TYVEX (DuPont)substrate which is made from a tough woven polyolefin material availablein various thicknesses and porosities. If such material having asuitable porosity is used, contacts 72 and 74 and feed-through 76 can beformed by a single printing operation with conductive ink on one side ofthe TYVEX sheet. Due to the porosity of the TYVEX, the ink willpenetrate to the other side of the TYVEX and form both contacts andfeed-through in one operation.

For probe 62 in the embodiment of FIG. 3A, substrate 68 is replaced by arelatively rigid PC board which includes conducting wires to attach eachof electrical contacts 72 to one of the pins of connector 51 (FIG. 3A)and the rest of the connecting structure of FIG. 5A may be omitted. Itshould be noted that the choice of using the structure of FIG. 3A or 3B(i.e., probes 62 or 62′) is an economic one depending on the cost ofmanufacture of the probes. While probe 62 is structurally simpler, thedisposable portion of probe 62′ is believed to be less expensive tomanufacture in large quantities. Since it is envisioned that the probeswill be used in large quantities and will preferably not be reused oneor the other may be preferable.

The other side of the probe is also protected by a cover plate 88 (FIGS.5A and 5B) which is attached using any bio-compatible adhesive to theouter edges of dividers 66 (FIG. 5A) and/or to the hydrogel, which ispreferably moderately tacky. In one preferred embodiment of theinvention, the inner surface of the cover plate 88 is provided with anelectrically conductive layer so that the impedance of each sensingelement from the outer surface of the hydrogel (or conductive gel) tocontact 82, can be measured using an external source. In addition, if aknown impedance is connected between the conductive layer and areference point or a source of voltage, the sensing elements can betested in a measurement mode similar to that in which they will finallybe used.

Alternatively, a film RC circuit or circuits may be printed on the innersurface of plate 88 to simulate an actual impedance imaging situation.Alternatively, plate 88 may be provided with contacts at each sensinglocation, and circuitry which may simulate a plurality of actualimpedance imaging situations. Such circuitry may include external orintegral logic such as programmable logic arrays and may be configurableusing an external computer interface. The simulation may provide adistinct RC circuit for each sensing element or may provide a sequenceof different circuits to each sensing element to simulate the actualrange of measurements to be performed using the probe.

FIG. 5B shows a preferred embodiment of cover sheet 88 (indicated on thedrawing as 88′) and its mode of attachment to both the multi-elementsensor and the PC board. In this embodiment a multi-element probe 62″ isoptionally further attached to PC board 80 by an adhesive frame 210which may be conductive or non-conductive, and which assists inpreventing entry of water or gel under sensor 62″. Sensor 62″ ispreferably further aligned to PC board 80 by one or more holes 222 withone or more pins 204, which are permanently attached to PC board 80 orto a surface adjacent to PC board 80. While pin 204 is shown as beinground, using rectangular, triangular, hexagonal pyramidical or othershapes provides additional alignment of the sensor. In general the upperportion of the pin should be curved for improved electrical contact asdescribed below.

The upper exposed surface of pin 204 is conductive, preferably curvedand is preferably connected to a signal reference source by a conductor202 in PC board 60. Cover sheet 88′ is made of a single integral sheetof easily deformable polyethylene, Mylar or other suitable plastic.Cover sheet 88′ is preferably removably attached to the upper side ofmulti-element probe 62″ by a continuous frame of adhesive 225, whichneed not be conductive, but which seals around a lip where cover 88′contacts probe 62″ to protect the quality and sterility of array 230 andto maintain the moisture content of any medium filling wells 70. Cover88′ is coated on the side facing probe 62″ with a conductive layer 231,such as any of the various metallic coatings, for example, aluminum orthe thin film coating described above.

Cover 88′ is preferably formed after conductive coating, by embossing,vacuforming or other means, to have depressions 233 in the cover locatedover corresponding wells 70. The depressions are approximately centeredon the center of the wells and held a small distance “61” above thesurface of the hydrogel or gel, by means of relatively high sidewalls226 which are formed at the same time as depressions 233. Furthermore,the surface of cover 88′ preferably has a concave shape to match therounded conductive contact surface of pin 204, from which it is held ata distance “δ2”. Distances δ1 and δ2 are selected to minimize unintendedphysical contact between the conductive inner surface of the cover, thecontacts in the wells and pin 204, for example, during storage andhandling prior to use, which might cause corrosion over time due toelectrochemical processes.

Distances δ1 and δ2 are also preferably selected so that application ofa nominal force (preferably about one kilogram) against a flat outersurface 232 of cover 88′, such as by a weighted flat plate, willestablish contact between the inner coating 231 and the upper surface ofpin 204 and with the sensing elements or the gel in the wells.

By establishing this contact, the conductive inner surface 231 isconnected, on the on hand to signals source contact 202 and with eachsensing element. If the coating is conductor, the sensing elements areall excited by the signal on line 202; if it is a thin film circuit, thecontact is via the thin film circuit. In either event, if line 202 isexcited by a signal, the signal will be transmitted to each of thesensing elements, either directly, or via a known impedance.

In either case, the multi-element array can be tested by the system andany residual impedance noted and corrected when the probe is used forimaging. If the residual impedance of a given sensing element is out ofa predetermined specification, or is too large to be compensated for,the multi-element probe will be rejected. Furthermore, the computer maybe so configured that imaging may only take place after determination ofthe contact impedance of the sensing elements or at least ofverification that the probe impedances are within a predeterminedspecification.

While pin 204 is shown as being higher than the top of the wells, thepin may be at the same height as the wells, or even below the wells withthe cover being shaped to provide a suitable distance “δ2” as describedabove.

In an alternative embodiment of the invention, the contact surfacecorresponding to pin 204 is printed on or attached to the surfaceholding the sensing elements, with contact to the PC board being via athrough contact in substrate 68, as for the sensing elements.

In yet another embodiment of the invention, the conductive contactsurface associated with pin 204 is on the surface holding the sensingelements adjacent to pin 204. Pin 204 supports this surface and contactsthe contact surface via one, or preferably a plurality of throughcontacts. Pin 204 is designed to match the contour of the contactsurface and preferably, by such matching, to provide additionalalignment of the probe on the PC board.

To avoid drying out of the Gel or other potential hazards of limitedshelf life, the quality of any of the aforementioned versions of thedisposable electrode arrays can be assured by incorporating anidentification code, preferably including manufacturer and serial numberinformation and date of manufacture. In a preferred embodiment, theinformation is coded in a bar code printed on each disposable probe,which is packaged together with at least one other such probe (typically5–50 probes) in the same packet, which also has the same bar code. A barcode reader, interfaced with the system computer, reads themanufacturing information on the packet and each probe, checking fordate and compliance and permitting recording only for a number ofpatients equal to the number of probes in the packet.

In a preferred embodiment of the invention a bar code may be placed onthe individual disposable electrode arrays which can be read by a barcode reader installed in or under the PC board, for example nearreference numeral 83 of FIG. 5B.

While the invention has been described in conjunction with the preferredembodiment thereof, namely a generally flat, somewhat flexiblestructure, suitable for general use and for breast screening, othershapes, such as concave structures (e.g., brassiere cups) or the likemay be preferable, and in general the shape and configuration of thedetectors will depend on the actual area of the body to be measured. Forexample cylindrical arrays can be useful in certain situations, forexample in intra-rectal examinations of the prostate or colon or insidevessels. In this context, a probe according to the invention is alsouseful for measurements inside the body, for example gynecologicalmeasurements or measurements in the mouth, where the probe is insertedinto a body cavity and contacts the lining of the cavity, and probeshaving shapes which correspond either flexibly or rigidly to the surfacebeing measured can be used. For example, a multi-element probe inaccordance with the invention may be incorporated into or attached to alaparoscopic or endoscopic probe.

Furthermore, sterilized probes can be used in invasive procedures inwhich the probe is placed against tissue exposed by incision. In thiscontext, the term “skin” or “tissue surface” as used herein includessuch cavity lining or exposed tissue surface.

In a preferred embodiment of the invention, PC board 80 and as manyelements as possible of probe 62′ (or the board of probe 62) are made oftransparent or translucent material, so as to provide at least somevisibility of the underlying tissue during placement of probe 62. Thoseelements of the probe and conductors in the PC board, to the extent thatthey are opaque should be made as small as practical to provide thelargest possible view to a technician or clinician to aid in placementof the probe. Furthermore, probe 62 is slidably displaceable when usedwith the above-mentioned conductive gel to permit moderate lateraladjustment of the probe position, to aid in placement, to ensure goodcontact between each element and the tissue surface to be measured, andto enable the user to rapidly verify whether detected abnormalities areartifacts due to poor contact or are genuine objects, since artifactsremain stationary or disappear entirely when the probe is moved whilegenuine objects just move in a direction opposite to the direction ofmovement of the probe.

The general shape and size of the multi-element probe and the size ofthe conductive sensing elements will depend on the size of the area tobe measured and on the desired resolution of the measurement. Probematrix sizes of greater than 64×64 elements are envisioned for viewinglarge areas and probes which are as small as 2×8 elements can be usefulfor measuring small areas. Element size is preferably between 2 mmsquare and 8 mm square; however, larger sizes and especially smallersizes can be useful under certain circumstances. For the breast probe 62described above, 24×32 to 32×40 elements appear to be preferred matrixsizes.

FIG. 6A shows a perspective view of a hand held probe 100 in accordancewith a preferred embodiment of the invention. Probe 100 preferablycomprises two probe heads, a larger head 102 and a zoom sensor head 104.A handle 106 connects the sensor heads, houses switching electronics andprovides means for holding and positioning the probes. Handle 106 alsooptionally incorporates a digital pointing device 105 such as atrackball, pressure sensitive button or other such joystick device.Incorporation of a pointing device on the probe enables the operator tocontrol the system and input positional information while keeping bothhands on either the probe or patient. As d scribed below, the digitalpointing device can be used to indicate the position on the patient'sbody at which the image is taken.

FIG. 6B shows a partially expanded bottom view of probe 100 of FIG. 6A,in accordance with a preferred embodiment of the invention. Whereapplicable, like parts of the probes throughout this disclosure aresimilarly numbered. Starting from the bottom of FIG. 6B, the top half ofa housing 108A has a well 110 formed therein. A clear plastic window 112is attached to the edge of well 110, and a printed circuit on arelatively transparent substrate, such as Kapton, designated byreference 80′ (to show its similarity to the corresponding unprimedelement of FIG. 5) is placed on window 112. A flexible print cable 114connects the contacts on printed circuit 62′ to acquisition electronics116. A cable 118 connects the acquisition electronics to the computer. Asecond similarly constructed, but much smaller zoom sensor probe head isattached to the other end of probe 100. Either of the larger or smallerheads may be used for imaging.

A lower half of housing 108B, encloses electronics 116 and print 80′,whose face containing a series of contacts 82′, is available through anopening 120 formed in the lower housing half 108B. A mounting frame 122having two alignment pins 124 holds print 80′ in place. Mounting andconnecting screws or other means have been omitted for simplification.

A disposable multi-element probe 62′, similar to that of FIG. 5 ispreferably mounted on the mounting frame to complete the probe.

FIG. 7A is a perspective view of a fingertip probe 130 in accordancewith a preferred embodiment of the invention as mounted on the finger132 of a user. Probe 130 may be separate from or an integral part of adisposable glove, such as those normally used for internal examinationsor external palpation. The fingertip probe is especially useful forlocalizing malignant tumors or investigating palpable masses duringsurgery or during internal examinations. For example, during removal ofa tumor, it is sometimes difficult to determine the exact location orextent of a tumor. With the local impedance map provided by thefingertip probe 130 and the simultaneous tactile information about theissue contacted by the probe, the tumor can be located and its extentdetermined during surgery. In a like fashion, palpable lumps detectedduring physical breast (or other) examination can be routinely checkedfor impedance abnormality.

FIG. 7B shows a flexible probe array 140 which is shown as conforming toa breast being imaged. Probe array 140 comprises a plurality of sensingelements 141 which contact the tissue surface which are formed on aflexible substrate. Also formed on the flexible substrate are aplurality of printed conductors 142 which electrically connect theindividual sensing elements 141 to conductive pads on the edge of thesubstrate. A cable connector 144 and cable 145 provide the finalconnection link from the sensing elements to a measurement apparatus.Alternatively, the flexible array may take a concave or convex shapesuch as a cup (similar in shape to a bra cup) which fits over andcontacts the breast.

The flexible substrate is made of any thin inert flexible plastic orrubber, such as those mentioned above with respect to FIG. 5A. Array 140is sufficiently pliant that, with the assistance of viscous gel orconductive adhesive, the sensor pads are held in intimate contact withthe skin or other surface, conforming to its shape.

FIG. 8 shows an intra-operative paddle type probe 140 used, in a similarmanner as probe 130, for determining the position of an abnormality inaccordance with a preferred embodiment of the invention. This probegenerally includes an integral sensing array 143 on one side of thepaddle. Preferably, the paddle is made of substantially transparentmaterial so that the physical position of the array may be determinedand compared with the impedance map.

FIG. 9 shows a laparoscopic probe 150 in accordance with a preferredembodiment of the invention. Probe 150 may have a disposable sensingarray 152 mounted on its side or the sensing array may be integral withprobe 150, which is disposable or sterilizable.

Multi-element probes, such as those shown in FIGS. 7, 8 and 9, arepreferably disposable or sterilizable as they are generally are usedinside the patients body in the presence of body fluids. In suchsituations, there is generally no need or desire for a conductive gel inaddition to the probes themselves. Generally, printed sensing elements,such as those printed with silver-silver chloride ink, or sensingelements formed of conductive silicone, hydrogel or of a conductivesponge may be used. While in general it is desirable that the sensingelements on these multi-element probes be separated by physicalseparators 66 (as shown in FIG. 5), under some circumstances thephysical distance between the elements is sufficient and the separatorsmay be omitted.

When performing a needle biopsy, a physician generally relies on anumber of indicators to guide the needle to the suspect region of thebody. These may include tactile feel, X-Ray or ultrasound studies orother external indicators. While such indicators generally give areasonable probability that the needle will, in fact take a sample fromthe correct place in the body, many clinicians do not rely on needlebiopsies because they may miss the tumor.

FIG. 10 shows a biopsy needle 154, in accordance with a preferredembodiment of the invention, which is used to improve the accuracy ofplacement of the needle. Biopsy needle 154 includes a series of sensingelements 156 spaced along the length of the probe. Leads (not shown)from each of these elements bring signals from the elements to adetection and computing system such as that described below. Elements156 may be continuous around the circumference, in which case theyindicate which portion of the needle is within the tumor to be biopsied.Alternatively, the electrodes may be circumferentially segmented (a leadbeing provided for each segment) so that information as to the directionof the tumor from the needle may be derived when the needle is notwithin the tumor. Such an impedance sensing biopsy needle can be used,under guidance by palpation, ultrasound, x-ray mammography or otherimage from other image modalities (preferably including impedanceimaging as described herein), taken during the biopsy or prior to thebiopsy to improve the accuracy of placement of the needle. Inparticular, the impedance image from the needle may be combined with theother images in a display. While this aspect of the invention has beendescribed using a biopsy needle, this aspect of the invention is alsoapplicable to positioning of any elongate object such as an other needle(such as a localizing needle), an endoscopic probe or a catheter.

Returning now to FIGS. 1–3 and referring additionally to FIGS. 11–14, anumber of applications of multi-element probes are shown. It should beunderstood that, while some of these applications may require probes inaccordance with the invention, others of the applications may also beperformed using other types of impedance probes.

FIG. 11A shows the use of the biopsy needle in FIG. 10 together with anoptional ultrasound imaging head in performing a biopsy. A breast 160having a suspected cyst or tumor 162 is to be biopsied by needle 154. Anultrasound head 164 images the breast and the ultrasound image, afterprocessing by an ultrasound processor 166 of standard design is shown ona video display 168. Of course, the ultrasound image will show thebiopsy needle. The impedance readings from probe 154 are processed by animpedance processor 170 and are overlaid on the ultrasound image of thebiopsy needle in the display by a video display processor 172.

In one display mode, the portions, as shown in FIG. 11B of the needlewhich are within the tumor or cyst and which measure a differentimpedance from those outside the tumor, will be shown in a distinctivecolor to indicate the portion of the needle within the tumor or cyst. Ina second display mode, the impedance measured will be indicated by arange of colors. In yet a third embodiment of the invention, in whichcircumferentially segmented sensing elements are employed, the impedanceprocessor will calculate radial direction of the tumor from the needleand will display this information, for example, in the form of an arrowon the display.

The image sensing biopsy needle can also be used with one or moreimaging arrays (28, 30) such as those shown in FIG. 6 or FIG. 3B toimpedance image the region to be biopsied during the biopsy procedure.Alternatively, at least one of the arrays can be an imaging array of thenon-imp dance type. In one preferred embodiment, shown in FIG. 11C, theneedle is inserted through an aperture (or one of a plurality ofapertures) 174 in a multi-element probe which is imaging the region. Theregion may, optionally, be simultaneously viewed from a different angle(for example at 90° from the probe with the aperture) with an otherimpedance imaging probe. In the case that both arrays 28 and 30 areimpedance imaging arrays, the biopsy needle or other elongate object caneither have impedance sensing or not, and the two images help direct itto the region. The probe with one or more apertures is sterile andpreferably disposable. This biopsy method is shown, very schematically,in FIG. 11C.

In an alternative preferred embodiment of the invention, only theperforated plate through which the needle or elongate object is passedis an imaging array. In this case the array through which the needlepasses give a two dimensional placement of the impedance abnormalitywhile an imaging or non-imaging impedance sensor on the needle gives anindication of when the needle has reached the region of impedanceabnormality, as described above.

Alternative guiding systems for frontal and lateral breast biopsy or forguiding an elongate element to a desired impedance region of the bodyare shown in FIGS. 11D and 11E, respectively.

FIG. 11D shows a system for in which two relatively large platemulti-element probes 28, 30 are placed on opposite sides of the desiredtissue, shown as a breast 160 of a prone patient 161. Sensor arrayprobes 28 and 30 are held in position by positional controller 181 viarotatable mounts 191. A mount 198 positions a biopsy needle 199 withinthe opening between probe arrays 28 and 30, and is operative to adjustits height. A suspicious region 183 which is located at positions 184and 185 on arrays 28 and 30 respectively as described herein, whichinformation is supplied to a CPU 197, which determines the position ofthe suspicious region for controller 181. The controller then insertsthe needle into the suspicious region, for example, to take the biopsy.Biopsy needle 199 is preferably of the type shown in FIG. 10 to furtheraid in positioning of the needle. As indicated above, this is notrequired for some embodiments of the invention.

Alternatively, biopsy needle 199 may be inserted through holes formedbetween the elements of probes 28 and/or 30 as described above.Furthermore, while automatic insertion of the biopsy needle is shown inFIG. 11D, manual insertion and guidance based on impedance imagesprovided by the probes is also feasible.

FIG. 11E shows a system similar to that of FIG. 11D in which the imagingand biopsy needle insertion is from the side of the breast, rather thanfrom the front. Operation of the method is identical to that of FIG.11D, except that an additional probe 29 may be provided for furtherlocalization of suspicious region 183. Alternatively, one or two of theprobes may be substituted by plates of inert material for holding andpositioning the breast.

It should be noted that while the breast has been used for illustrativepurposes in FIGS. 11A through 11S, the method described is applicable toother areas of the body, with necessary changes due to the particularphysiology being imaged.

It should be understood that one or more of the elements on the needlemay themselves be electrified to cause them to “light-up” on the image.This electrification may be AC or DC may be the same or different fromthe primary image stimulus, may have a single frequency or a complexform and may be applied in a continuous or pulsed mode. If one or moreof the sensing elements is used in this manner, said elements arepreferably alternatively used to apply an electrification signal and tofunction as sensors, i.e., to sense signals from the primary stimulus.

FIG. 12 shows, very schematically, the intra-operative probe of FIG. 8combined with a video camera 256 to more effectively correlate theimpedance measurement with the placement of the probe on the body. Anintra-operative probe 140 preferably having a number of opticallyvisible fiduciary marks 146 is placed on the suspect lesion or tissue. Avideo camera 256 sequentially views the area without the probe and thesame area with the probe in place and displays a composite image on avideo display 258 after processing by a processor 260. Processor 260receives the impedance data from probe 140, determines the positions ofthe fiduciary marks from the video image and superimposes the impedanceimage on the video image, with or without the probe, which is displayedon display 258.

FIG. 13 shows a laparoscopic or endoscopic probe 250 used in conjunctionwith a fiber-optic illuminator/imager 252. In this embodiment, thelaparoscopic impedance probe, which is formed on a flexible, preferablyextendible paddle, is viewed by the illuminator/imager which ispreferably a video imager, which is well known in the art. Probe 250 canbe either round or flat, depending on the region to be imaged. When theimager views a suspicious lesion or tissue, probe 250 is extended todetermine the impedance properties of the lesion. The combination ofprobe 250 and imager 252 may be incorporated in a catheter 254 or otherinvasive element appropriate to the region of the body beinginvestigated.

Optically visible fiduciary marks 253 on probe 250 are preferably usedto determine the position of probe 250 within the video image of thetissue seen by fiber-optic illuminator/imager 252, in a manner similarto that discussed above with respect to FIG. 12.

In a preferred embodiment of a system using any of the biopsy needle,intra-operative probe, finger tip probe or other embodiments describedabove, an audible sound proportional to an impedance parameter measuredby the needle or other sensor in or on the body is generated by thesystem computer. This feature may be useful in situations where theprobe is placed in locations which are difficult to access visually,such as suspected lesions during surgery. Such an audible sound couldinclude any kind of sound, such as a tone whose frequency isproportional to the measured parameter or similar use of beeps, clicks,musical notes, simulated voice or the like. This feature can also beused for non-surgical procedures such as rectal, vaginal or oralexaminations, or other examinations.

FIG. 16 shows methods useful for estimating the depth of a lesion andalso for determining if a image contains a true lesion or an artifact.

A breast or other region 160 is imaged by a probe 270, for example, theprobe of FIGS. 1–3 or FIGS. 6A and 6B. The depth of a local impedancedeviation can be estimated by palpating the breast or other region by afinger 272 or a plunger 274. The displacement of the local deviation onthe image will be maximized when the palpation is at the same level asthe lesion. It should also be understood that, where palpation causesmovement of the local deviation on the impedance image, this is anindication that the deviation is “real” and not an artifact.

In a similar manner, application of variable compression to the imagingprobe will result in a variation of the distance from the probe todeviation under the probe. This distance variation will cause acorresponding variation in the size and intensity of the deviation, thushelping to verify that the deviation is not artifactal.

Alternatively or additionally, the probe can be moved along the surfaceof the tissue without moving the tissue. In this case, surface effectswill have a tendency to either disappear or to move with the probe(remain stationary in the image) while real anomalies will move, on theimage, in the opposite direction from the movement of the probe.

Alternatively or additionally, the probe and the tissue can be movedtogether without moving the underlying structure (such as the bones).Tissue lesions will remain relatively stationary in the image while boneartifacts will move in the opposite direction.

In operation, a system according to the present invention measuresimpedance between the individual sensing elements and some referencepoint (typically the signal source point) at some other place on thebody. Generally, in order to produce an interpretable impedance image,the sensing elements in the multi-element probe should detectdistortions in the electric field lines due solely to the presence of alocal impedance difference between embedded tissue of on type (forexample, a tumor) and surrounding tissue of another type (for example,normal adipose tissue).

To avoid distortion in the field lines, the reference point is typicallyplaced far from the sensor array, all sensing elements are all at groundor virtual ground, and the current drawn by the elements is measured.Since the probe is at ground (an equipotential) the electric field lines(and the current collected by the elements) are perpendicular to thesurface of the multi-element probe. In principle, if there are novariations of impedance below the probe, each element measures theintegrated impedance below the element. This first order assumption isused in the determination of the position and/or severity of a tumor,cyst or lesion. It is clear, however, that the multi-element probecovers only a portion of even the organ which is being imaged. The areaoutside the area of the probe is not at ground potential, causing thefield lines to bend out at the periphery of the probe, biasing the edgeof the impedance image.

To reduce this effect, a conductive “guard ring” is provided around theedge of the imaged area to draw in and straighten the field lines at theedge of the imaged area. This guard ring, if one is desired, can consistof merely ignoring the, presumably distorted, currents drawn by theelements at (or near) the edge of the probe and ignoring themeasurements made by these elements. In general, while the use of aguard ring reduces the edge effect at the edge of the field, it is stillgenerally necessary to determine values for comparison or determinationof polychromic values near the ring based only on pixels near the ringand not on the image as a whole.

Furthermore, to possibly reduce the baseline impedance contributed tothe local impedance image by tissue between the remote signal source andthe region near the probe, an additional reference electrode may beplaced on the patient's body relatively near the multi-element probe.For example, if the source is placed at the arm of the patient and thebreast is imaged from the front, a reference electrode for sensing areference voltage can be placed at the front of the shoulder of thepatient. The measured impedances are then reduced by the impedance valueof the reference electrode. Alternatively, the impedance values of theelements of the multi-element probe are averaged to form a referenceimpedance, and the display of the impedance map is corrected for thisreference impedance.

One way to substantially avoid at least some of the above mentionedproblems is to use the apparatus shown in FIGS. 1–3. As indicated above,the apparatus incorporates two probe heads 28 and 30. The breast to beimaged is placed between the probe heads and the breast is compressed bythe heads (although generally to a lesser degree than in X-Raymammography) so that the breast forms a relatively flat volume and fillsthe region between the probes. It should be noted that, if the currentis measured at each of the sensing elements in both probes, then twosomewhat different images of the same region are generated. Avoidance ofthe problems also results when the two multi-element probes are notparallel as described above.

It should be noted that when used on breasts, the images produced by thepair of large, flat probes of FIG. 3 have the same geometricconfiguration as standard mammograms. Furthermore if used in the samecompression orientations, the impedance images can be directly comparedto the corresponding mammograms. In one preferred embodiment of theinvention, mammograms corresponding to the impedance images to be takenare digitized, using film scanning or other digitization means known inthe art, and entered into the system computer. If the mammogram isalready digital, such as may be provided by a digital mammogram, theimage file can be transferred from the mammogram.

The mammograms and impedance images can be overlaid or otherwisecombined to form a single image. Such an image could highlight thoseareas of the mammogram in which the impedance is particularly low orhigh. Such a combined image thus presents two independent readouts(impedance and radiographic density) of the same well defined anatomicalregion in a known geometric orientation, to facilitate interpretation,correlation with anatomy and localization.

It is well known that the resolution of objects in an impedance image isreduced with distance of the object from the probe. Thus, it is possibleto estimate the distance of the object from the two probes based on therelative size of the same object on the two different probes. Asindicated above, two opposing views of the breast may be taken. Thiswould provide further localization of the object.

In one mode, the sensing elements of one probe are all electronicallyfloating while the elements of the other probe are at a virtual ground(inputs to sensing electronics), and a remote signal source is used, aspreviously described. After an image is obtained from the one probe, theroles of the two probes are reversed to obtain an image from the otherprobe.

Alternatively, if all of the elements of one of the flat probes areelectrified to the same voltage and the measuring probe is kept atvirtual ground, the currents drawn from and received by the elements ofboth probes form a two dimensional admittance image of the regionbetween the probes.

In a further preferred embodiment of the invention, one or a few closelyspaced sensing elements on one of the probes is electrified, and theothers are left floating. This would cause a beam-like flow of currentfrom the electrified elements to the other sensing elements on the otherprobe. The object would disturb this flow causing impedance variationswhich are strongest for those elements which are in the path of thecurrent disturbed by the object. If a number of such measurements aremade with, each with a different group of electrodes being electrified,then good information regarding the position of the object can beobtained;

In practice, as indicated above, orthogonal views of the breast aretaken giving additional position information.

In preferred embodiments of the invention the breast is imaged at aplurality of frequencies and both the real and imaginary parts of theimpedance are calculated. The sensitivity of the detection of malignanttissue is a function of frequency, and, for a particular frequency, is afunction of the impedance measure or characteristic used for imaging,for example, real part of the impedance (or admittance), imaginary partof the imp dance (or admittance), absolute value of the impedance (oradmittance), phase of the impedance (or admittance), the capacitance orsome function of the impedance or of admittance components.

In a practical situation, an impedance measure should give the maximumcontrast between a malignancy and non-malignant tissue. It is thereforedesirable to determine the frequency or combination of frequencies whichgive maximum detectability and to determine it quickly. One method ofdetermining the frequency is to perform swept frequency measurements andto use the frequency or combination of frequencies which results in thebest contrast. Alternatively, a number of images taken at relativelyclose frequencies can be used. It is believed that for many purposes, atleast four samples should be taken in the range between and including100 and 400 Hz and, preferably, at least one or two additional imagesare taken at frequencies up to 1000 Hz.

A second method is to use a pulsed excitation and Fourier analysis todetermine impedance over a range of frequencies. The optimum frequencyor frequencies determined from the swept or pulsed measurement are thenused in a single or multiple frequency measurement. A pulse shape whichhas been found useful in this regard is a bi-polar square pulse havingequal positive and negative going pulses of 5–10 millisecond durationand fast rise and fall times.

A number of measures of the impedance, as described below, have beenfound useful for comparing different areas of the image. Generally, itis useful to display a gray scale or pseudo-color representation of thevalues of the impedance measure, either on a linear scale or where thesquare of the impedance measure is displayed. Also useful is an“absorption scale” where the value of an impedance measure, v, isdisplayed as:d(v)−(max−1)*(exp(v*(max−1)−1))/(e−1),where max is the maximum normalized value of v. Generally, the displayis most useful when the measure is normalized, either by division orsubtraction of the minimum or average value of the measure in thedisplay or the estimated standard deviation or other measure of variancefor the image.

Furthermore, the display may be automatically windowed to include onlythose values of the impedance measure actually in the image, or toinclude a relative window of selectable size about the average value ofthe impedance measure. The range of values to be displayed may also bedetermined using a baseline average value measured at a region remotefrom irregularities, i.e., remote from the nipple of the breast.Alternatively, the baseline average may be a predetermined average valueas measured for a large group of patients. Alternatively, a referenceregion on the image may be chosen by the user to determine the baselineaverage to be used for windowing.

While the display may show the exact measure for each pixel as isconventional, for example, in displays of nuclear medicine images, in apreferred embodiment of the invention the display is an interpolatedimage formed by quadratic or cubic spline interpolation of the impedancemeasure values. This type of display removes the annoying checkerboardeffect of the relatively low resolution impedance image without anysubstantial loss of spatial or contrast detail.

The measures of impedance which have been found useful for comparingdifferent areas of the image may be grouped as single frequency measuresand polychromic measures.

Single frequency measures include the admittance, capacitance,conductance and phase of the admittance and its tangent. These measuresmay be measured at some predetermined frequency, at which thesensitivity is generally high, or at a frequency of high sensitivitydetermined by a preliminary swept or pulsed measurement. Cancertypically has significantly higher phase than the average surroundingtissue, with greatest difference at low frequencies such as 100 Hz, butoften significant up to 5 KHz.

Polychromic impedance measures are based on measurements at more thanone frequency, such as on a spectral curve based on fitting a set ofcapacitance (C) and conductance (G) values determined at a plurality offrequencies using linear interpolation, quadratic interpolation, cubicspline, band limited Fourier coefficients, or other methods known in theart.

One polychromic measure is a spectral width measure. For a given pixelor region of interest the value of C parameter falls (and the Gparameter rises) with frequency. The spectral width of the spectrum isthe width to a given percentage fall in the C value as compared to thevalue at some low frequency, for example 100 Hz. If the parameter doesnot fall by the given percentage in the measured range it is assigned animpedance measure equal to the full measured bandwidth. Similarly, thespectral width of the G-spectrum is the width to a given rise in theG-Parameter compared to the value at some low frequency, for example 100Hz, or alternatively, the fall in G with decreasing frequency comparedto the value at some high frequency, for example 3000 Hz.

A second polychromic measure is a spectral quotient in which theimpedance measure is the ratio of the measured value of G or Cparameters at two preset frequencies, which may be user selected, orwhich may be selected based on the swept or pulsed measurementsdescribed above. This measure, as all of the others may be displayed ona per-pixel basis or on the basis of a region of interest of pixels,chosen by the user.

A third type of polychromic measure is based on a Relative DifferenceSpectrum determination. In this measure, the capacitance or conductancefor a given region of interest (or single pixel) is compared to that ofa reference region over the spectrum to determine a numerical differencebetween the two as a function of frequency. The thus derived RelativeDifference Spectrum is then analyzed. For example, a spectral widthmeasure as described above has been found to be a useful measure ofabnormalities. Normally the width is measured where the relativedifference spectrum passes from positive to negative, i.e., where the Cor G is equal to that of the reference region. For capacitance, thisspectrum width is designated herein as the Frequency of CapacitanceCrossover (FCX). This measure has been found to be especially useful inclassification of tissue types as described below.

A fourth type of polychromic measure is based on a Relative RatioSpectrum determination. This is similar to the Relative DifferenceSpectrum, except that the ratio of the values between the reference areaand the region of interest is used. A spectral width measure can bedetermined for this spectrum in the same manner as for the Relativedifference Spectrum. Normally, the width is measured where the ratiois 1. This width is the same as the width of Relative DifferenceSpectrum at the zero (cross-over) point.

A fifth type of polychromic measures are the Positive and NegativeIntegrated Relative Difference for Capacitance and/or Conductanceabbreviated C (for capacitance) or G (for conductance) NIRD or PIRD.These values are calculated by adding up the negative (or positive)deviations of the capacitance (or conductance) values in the area ofabnormality from those of a representative value (or range of values) ofthe capacitance (or conductance) at the various measured frequencies.This representative value or range is determined from pixel values inthe image selected to exclude exceptionally high or low capacitance (orconductance) values. The same pixel may have both a C-NIRD and a C-PIRDif its capacitance deviates positively from the representative value forsome subset of the frequencies and negatively from the representativevalue for a different subset of the frequencies. The C-NIRD, C-PIRD andG-NIRD measures have been found to be especially useful forcharacterizing tissue type as described below.

A sixth polychromic measure is the integrated phase. For a given pixelin the image, the phase is measured at a plurality of frequencies in adesired frequency range, typically 100 to 5000 Hz. The integrated phaseis the sum of the phase over a number of frequencies, typically about 13frequencies between 100 and 3200 Hz. Alternatively, integration may beperformed using the trapezoidal rule or by integrating anotherfunctional fit to the sampled values in the desired frequency range.Cancer typically has significantly higher integrated phase. Theintegrated tangent of the phase is an alternative measure of thismeasure.

A seventh polychromic measure is the integrated phase difference. In agiven image, the phase of each pixel is measured at each of a pluralityof frequencies in a desired frequency range, typically 100 to 5,000 Hzand the median or average phase determined for the image at eachfrequency. In calculating the median or the average, the highest andlowest values are preferably excluded by using such methods as (1)including only pixels whose values lie within a specified range of thepixel histogram, such as only those between the 25 and 75 percentilephase values for the image. For each frequency, the median or averagefor the image is subtracted from the phase value for each pixel. Thisresults in a phase difference spectrum which is positive for frequencieswhere the pixel value is higher than average and negative where it islower. The sum of the phase differences is the integrated phasedifference (IPD), and the sum of all the positive phase differences isthe integrated positive phase difference. Both these measures aresignificantly higher for cancer than for normal surrounding tissues.

An eighth polychromic measure is the specific frequency. The phase ofeach pixel is measured at each of a plurality of frequencies in adesired frequency range, typically 100 to 5000 Hz. The resultantspectrum is fitted to a piecewise linear function, a spline function ora functional fit as known in the art. The lowest frequency at which thephase reaches 45 degrees is defined as the Specific Frequency. SpecificFrequency is typically lower for cancer (range of 100 to 800 Hz) thanfor normal surrounding tissue (range of 1200 Hz to several kilohertz.The RC time constant evaluated at the specific frequency is also auseful related polychromic measure, being lower for cancer.

A ninth polychromic measure is the capacitance spectral slope, i.e., thederivative of the capacitance curve (or of the log capacitance curve) asa function of frequency, evaluated at a given frequency. This isconsidered to be a polychromic measure, since its determination requiresthe measurement of the capacitance at more than one point. CapacitanceSpectral slope in the range 100 to 5000 Hz is typically negative andtypically has a higher absolute value in cancer vs. normal pixels,particularly at low frequencies such as 100 to 500 Hz.

A tenth polychromic measure is the conductance spectral slope, thederivative of the conductance (or of the log conductance) evaluated at agiven frequency. Conductance Spectral slope in the range 100 to 5000 Hzis typically positive and typically has a lower value in cancer vs.normal pixels, particularly at low frequencies such as 100 to 500 Hz.

The NIRD and PIRD measures may be defined in various ways. For example,the deviations from the representative value may be used in thecalculation only when they exceed some minimum value. The deviation maybe expressed as a the actual numerical deviation or more preferably as aratio or as a deviation normalized to some “standard” deviation of thecapacitance or conductance which is characteristic of normal tissue, asdefined below.

Preferably, the value representative of normal tissue is derived bylooking at pixel values representative of some proportion of the totalnumber of pixels in an image. For example if a 8×8 image were used, andthe anomalous portion occupied less than 25% of the image, the 16 pixelshaving each of the highest and the lowest values would not beconsidered. The representative value would then be, for example, themean value of capacitance or conductance of the remaining pixels and astandard deviation would be the range of pixel values among the 32pixels which are considered.

This determination is based on the practical consideration that almostalways at least 50% of the pixels represent normal tissue. It is clearthat many other measures of the representative value and of the“standard” deviation will be equally useful in the practice of theinvention and that such measures may be computed in many different ways.Furthermore the range of pixels which are considered “normal” may beadjusted depending on the type of tissue actually being measured. Forexample, for tissue having large areas with apparently high values, arange of pixel values such as, for example 20%–50% (instead of the25%–75% described above) may be more useful.

Another potentially useful polychromic parameter is the slope of thelogarithm of the capacitance of a given pixel or region as a function offrequency. This curve generally has a shape which is predominantlylinear. Alternatively, the ratio of the slope of the capacitance of theparticular pixel to the slope of the capacitive representative value maybe useful.

Furthermore, it may be useful to consider, as an additional polychromicmeasure, the maximum of one of the other polychromic measures, forexample, the capacitance, conductance, Relative Difference Spectrum,Relative Ratio Spectrum, etc.

In general, some pixels are excluded from the characterization. Thesewould include “No-Contact” pixels having near zero conductance andcapacitance values and “Contact Artifactal Hot Spots” which are pixels,with elevated capacitance or conductance values, next to no contactpixels.

In impedance measurements of the breast in both men and women, normalbreast tissue has a low capacitance and conductivity, except in thenipples, which have a higher C and G values than the surrounding tissuewith the maximum obtained at the lowest frequency recorded, typically100 Hz. The nipple capacitance and conductance remains very much higherthan the surrounding tissue up to about 1400 Hz for fertile patients andup to about 2500 Hz for older patients (which is reduced to 1400 Hz forolder patients by estrogen replacement therapy). These frequenciesrepresent the normal range of spectral widths for the Relative andDifference Spectra. Tumors can be recognized by very high C and Grelative ratio or relative difference values at all frequencies below1000 Hz and moderate difference or ratio values for frequencies up to2500 Hz or even higher.

Capacitance and conductance values are measured by comparing theamplitude and phase of the signal received by the sensing elements.Knowing both of these measures at the same points is useful to properclinical interpretation. For example, as illustrated below in FIG. 14, aregion of elevated conductivity and reduced capacitance (especially atrelatively low frequencies, most preferably less than 500 Hz, bygenerally below 2500 Hz and also below 10 kHz) is associated withbenign, but typically pre-cancerous a typical hyperplasia while, asshown in FIG. 15, cancer typically has both elevated capacitance andconductivity over, generally, a wide frequency range, as compared to thesurrounding tissue. Proper differential diagnosis is aided by having thefrequency samples be close enough together so that changes in theconductivity and capacitance in the low frequency range can be tracked.This also requires the display of both capacitance and conductance orthe use of an impedance measure which is based on an appropriatecombination of the two.

Methods for calculating C and G are given in the abovementioned U.S.Pat. Nos. 4,291,708 and 4,458,694, the disclosures of which areincorporated herein by reference. A preferred embodiment of theinvention takes advantage of the calibration capability inherent in theuse of cover plates as shown in FIGS. 5A and 5B. It can be shown that ifthe received waveform is sampled at a fixed spacing, δ, such that Nsamples are taken in each cycle, then the real and imaginary values ofthe impedance can be determined as:G=Σ(g _(n)(V _((n+1/2N)) −V _(n)),andωC=Σ(c _(n)(V _((n+1/2N)) −V _(n)),where g_(n) and c_(n) are constants determined by a calibrationprocedure and V_(n) is the voltage measured at the nth sampling point(out of N). The first sample is taken at zero phase of the referencesignal.

One relatively easy way to determine the constants is to perform aseries of measurements when cover plate is in contact with the sensingelements as described above and a known impedance is placed between thetransmitter and the cover plate. Since N coefficients are required fordetermining g_(n) and c_(n) for each frequency, N values of admittanceand N measurements are required. For example, if N=4 (four samples percycle) four different measurements are taken and the sampled signalvalues are entered into the above equations to give N equations, whichare then solved for the values of the coefficients. The higher thenumber of samples, the greater the accuracy and noise immunity of thesystem, however, the calibration and computation times are increased.

Alternatively, fewer samples are taken and values for a number ofmeasurements are averaged, both in the calibration and clinicalmeasurements to reduce the effects of noise.

Artifactal abnormalities in the impedance image can be caused by suchfactors as poor surface contact or insufficient conductive coupling onsome or all of the sensing elements, the presence of air bubbles trappedbetween probe and tissue and normal anatomical features such as bone ornipple.

Bubbles can be recognized by their typically lower C and G valuescompared to background, often immediately surrounded by pixels with muchhigher C and G. Bubbles can be verified and eliminated by removing theprobe from the skin and repositioning it, and or by applying additionalconductive coupling agent. Contact artifacts can be determined andaccounted for in real time by translating the probe and viewing theimage as described above. Artifacts either disappear or remain fixedwith respect to the pixels, while real tissue features move, on theimage, in a direction opposite from the motion of the probe.Additionally, as described above, if the tissue beneath the skin isphysically moved, while the probe and skeletal structure is kept fixed,only real tissue features will move. If the feature remains static, itis either a skin feature or bone.

If as described above, the probe and the tissue are moved togetherwithout moving the underlying structure (such as the bones). Tissuelesions and surface effects will remain relatively stationary in theimage while bone artifacts will move in the opposite direction, thusdistinguishing them from other impedance deviations.

FIG. 14 shows one example of a display, according to a preferredembodiment of the invention. In this display, capacitance andconductivity images at two positions on a breast are shown, togetherwith an indication of the positions on the breast at which these imageswere acquired.

In particular, as seen in FIG. 15, the display includes the capabilityof displaying up to five sets of capacitance and conductance images inthe five sets of smaller squares. These images are associated with probeareas indicated as numbers 1–5 on the breast image shown in the display.In practice, the examiner manipulates a joystick or other digitalpointing device, such as device 105 shown in FIG. 6A. This device ismanipulated until a square is appropriately placed on the breast image.The examiner then presses a button which causes a pair of impedanceimages to be stored and displayed on the screen in an appropriatesquare, and the indicated position to be displayed on the physiological(breast) drawing. The small images are numbered from left to right.Preferably, the examiner can scale the physiological image so that thedimensions of the breast shown and the extent of the probe array arecompatible. It should be understood that during the placement of theprobe, real time images (acquired about once every 50–80 msec) of thecapacitance and the conductance are shown, for example in the largesquares to the left of the display.

FIG. 14, which represents an actual imaging situation shows, in theleftmost of the small images, a situation in which a small a typicalhyperplasia which was previously detected by other means. This positionshows an elevated conductivity and a very slightly reduced capacitance.In position 2, which is also shown in the two large squares to the rightof the display, a previously unsuspected area having acapacitance/conductance profile characteristic of a typical hyperplasiais detected.

FIG. 15 shows a study typical of multiple suspected sites of carcinoma(in positions 2 and 4). The images of position 4 are shown in enlargedformat at the left of the image. In these sites, both the capacitanceand conductance are elevated with respect to their surroundings.

Alternatively, a composite image such as the image of the sum of thecapacitance and conductance images, their product, their sum or theirratio can be displayed to give a similar indication of the type ofdetected anomaly. A color coded composite image can also be displayed,where, for example, the median value for each image would be black andwhere positive and negative values would have a particular color which,when combined would result in distinctive colors for suspect impedancedeviations.

The display shown in FIGS. 14 and 15 can be utilized to show a pluralityof images of the same region at a plurality of frequencies.Alternatively or additionally, the display can be utilized to show aplurality of different polychromic measures of the same region. Inaddition, using, for example, the fact, as described below with anexample, that a plurality of such measures can be useful in identifyingtissue type more accurately than can a single measure, the display mayinclude, inter alia, an image in which portions of the image isidentified by tissue type. For such an image, for example, the color ofportions of the map could represent the type of tissue and thebrightness the certainty of the identification. The type identificationand certainty would depend on the probability that a particular “mix” ofvalues of the polychromic measures are associated with a particulartissue type and that not all measures are always within the specifiedrange for any particular tissue type. In conjunction with the display ofsuch a map the individual polychromic measures may be displayed eithertogether or in sequence to make the determination of the tissue typemore certain.

One type of display of multiple polychromic images is to use a pseudocolor image of two or three colors, each of which represents one of themeasures. When a measure for a portion of the image meets the criteriafor a given tissue type it is displayed in its assigned color. When twoor more such criteria are met a different color is displayed, dependingon which of the criteria are met.

Another type of display shows the values of the measures as iso-contoursof varying brightness of a color assigned to the measure. Theconjunction of isocontour lines characteristic of a given tissue typemay then be recognized from isocontours.

Alternatively or additionally, the image can be a pseudo 3-D imagewherein each of the measures is delineated as a wire screen of a givencolor. This allows for the visualization of more than one measure at thesame time.

Alternatively, a map of immitance, or the real or imaginary part thereofis overlaid with indications, based on polychromic measures of thetissue type involved, as for example by color coding, by arrows withassociated legends or by other means to alert the operator to suspectedsites of tissue of specific types. Such measures may be calculatedautomatically or in response to a query from the operator in respect toan area of the image of which the is suspicious.

It has been found that certain immitance measures and combinations ofmeasures are characteristic of certain types of normal and abnormaltissue. In one example of the method four of the polychromic measuresdescribed above can be utilized separately or, more particularly, incombination to indicate the presence of certain normal or abnormaltissue. These four measures are CFX, G-PIRD, C-PIRD and C-NIRD measure.Other combinations of polychromic measures are also useful in indicatingtissue type.

It has been found that normal tissue, as expected, has low or zerovalues of all of the measures. Nipples and the infra-mammary ridge havea very high value of G-PIRD and C-PIRD together with zero to low valueof CFX and no G-NIRD. Ribs and the costo-chondral junction have lowvalues of C-PIRD and CFX, moderate to high values of G-PIRD and lowvalues of C-NIRD. Typical benign hyperplasia has a moderate to highvalue of C-NIRD and G-PIRD, a high value of CFX and no C-PIRD, whileprecancerous a typical hyperplasia has values in a range similar to thatof typical hyperplasia for C-NIRD, and G-PIRD but has a moderate valueof CFX and C-PIRD. This allows precancerous a typical hyperplasia to bedifferentiated from benign hyperplasia. Furthermore, cancerous tumorsappear to be characterized by medium to high values of C-PIRD and CFX,high values of G-PIRD and low values C-NIRD. Some tumors, especiallythose with very high C-PIRD have no C-NIRD.

The four measures, C-PIRD, C-NIRD, G-PIRD and CFX, form a fourdimensional space in which each set of measurements in designated by asingle point. In order to represent such a space on paper two orthogonalprojections of the four dimensional space are required. One such set oforthogonal projections is shown in FIGS. 18A and 18B. While theseprojections fully describe all four measures, they plot the measures inpairs only. Presenting the regions of the space which are characterizedby the various tissue types in a single drawing is possible since all ofthe measures have only positive (or zero) values. Since only positivevalues of the measures are allowed it is possible to combine these twoorthogonal projections, as in FIG. 18C, into a single projection inwhich each of the axes represents a positive value of one of themeasures. FIG. 18C shows the information in a redundant manner (i.e., itactually shows two orthogonal projections), however, it is useful sinceit shows all combinations of the various measures on a single figure.

It will be noted from FIGS. 18A–C and from the above discussion thatthere is some overlap between nipples (and Infra-mammary ridge) andtumors and also between ribs (and costo-chondral junction) and tumors.Where ambiguity does exist (i.e., in the relatively small overlap areasshown in FIG. 18C) the distinction can generally be made based on theanatomy of the portion of the patient being imaged. Thus, an ambiguoustumor/nipple far from the nipple would be classified as a tumor and atumor/rib far from the ribs would be classified as a tumor. Where theanatomy does not allow for a clear determination, such as for example atumor which is close to the nipple, an additional view and/or adifferent breast position, palpation or other methods of separating theanomaly from the normal tissue will generally remove the ambiguity.

While a particular impedance imaging system has been described as thebasis for determining the type of tissue underlying the anomalies (andcausing them) The method is also believed to be generally useful intissue type determination using other types of impedance imaging systemsand also in situations where no image is generated.

For example, the method is also potentially useful to determine tissuetypes in situations where either a single impedance probe is used orwhere the image is small and only anomalous areas are imaged. In thesecases the comparison for determining the measures is mad between thevalues of capacitance or conductance measured for the anomalous regionas compared to the capacitance or conductance measured for a nearbyregion known to be normal.

The method is also useful for determining the type of tissue which ispierced by a biopsy needle or contacted directly by a probe such as thefinger probe of FIG. 7A of the invasive probes of FIGS. 8–10. In thesecases a comparison may be made between values at the tissue to becharacterized and other “normal” tissue.

FIGS. 17A and 17B show a block diagram of a preferred embodiment of asystem 200 which incorporates a number of multi-element probes. Itshould be understood that the exact design of system for impedanceimaging will depend on the types of probes attached to the system andthe exact imaging modalities (as described above) which are used.

As shown in FIGS. 17A and 17B the preferred system can incorporatebiopsy needle probe 154, two plate probes 28, 30 such as those shown inFIGS. 1–3, scan zoom probe 100 such as that shown in FIG. 6A, conformalprobe 139 such as that shown in FIG. 7B, a bra-cup probe, finger/gloveprobe 130 such as that shown in FIG. 7A, laparoscopic probe 150 such asthat shown in FIG. 9 or an intra-operative probe 140 as shown in FIG. 8.Furthermore, when three probes are used as in FIG. 11E, provision ismade for attachment of a third plate probe. The position of the plateand needle probes is controlled by controller 181 as described inrespect to FIG. 11D.

The probes as connected via a series of connectors, indicated byreference numeral 302 to a selection switch 304 which chooses one ormore of the probes in response to a command from a DSP processor 306.Selection switch 304 switches the outputs of the probes, namely thesignals detected at the sensing elements of the probes (or amplifiedversions of these signals) to a set of 64 amplifiers 308, one amplifierbeing provided for each sensing element. For those probes, such as thelarge plate probes, which have more than 64 sensing elements, theselection switch will (1) sequentially switch groups of 64 sensingelements to amplifier set 308, (2) choose a subset of sensing elementson a coarser grid than the actual array by skipping some elements, asfor example every second element, (3) sum signals from adjacent elementsto give a new element array of lower resolution and/or (4) choose only aportion of the probe for measurement or viewing. All of these switchingactivities and decisions are communicated to the switch by DSP processor306 which acts on command from a CPU 312. The output of the amplifiersis passed to a multiplexer 307 where the signals are serialized prior toconversion to digital form by a, preferably 12-bit, A/D convertor 310. Aprogrammable gain amplifier 309, preferably providing a gain which isdependent on the amplitude of the signals, is optionally provided tomatch the signal to the range of the A/D convertor. The output of A/D310 is sent to the DSP for processing as described above. In a preferredembodiment of the invention DSP 306 is based on a Motorola MC 68332microprocessor.

While 64 amplifiers has been chosen for convenience and lower cost, anynumber of amplifiers can be used.

The DSP calculates the impedance results and send the results to CPU 312for display on a graphic data display 16, printing on a printer 18 orother output signals generation as described above by a light indicator314 or a sound indicator 316.

Alternatively, the DSP directs signal sampling and averages together thesamples or pre-processes them, sending the averaged or pre-processedsamples to CPU 312, which then performs the impedance calculations.

The CPU may also receive images from video camera 256, for example, whenused with an intra-operative probe, from an endoscopic optics and camerasystem 320, for example when the camera views the outer surface of thelaparoscopic probe or from an ultra sound imager 322, for example, inbiopsy performance as shown in FIGS. 11A and 11B. When an image isacquired from one of these cameras a frame grabber 324 is preferablyprovided for buffering the camera from the CPU. As described above, theCPU combines these images with the impedance images provided by one ormore probes for display or other indication to the operator.

FIG. 15 also shows a programmable reference signal generator 326 whichreceives control and timing signals from the DSP. The reference signalgenerator generates excitation signals which are generally supplied,during impedance imaging, to reference probe 13, which, as describedabove, is placed at a point (or at more than one point) on the bodyremote from the region of impedance measurement. Signal generator 312may produce a sinusoidal waveform, pulses or spikes of various shapes(including a bipolar square shape) or complex polychromic waveformscombining desired excitation frequencies. Appropriate impedancecalculations, in DSP 306 or in CPU 312, are implemented in accordancewith the waveform of the excitation.

Where a breast is imaged and one of the two plates is used as the sourceof excitation, as described above, the output of signal generator issent to the exciting plate (signal paths not shown for simplicity). Acurrent overload sensor 330 is preferably provided after the signalgenerator to avoid overloads caused by short circuits between thereference probe and the imaging probe or ground.

Also shown on FIG. 17A is an internal calibration reference 332 which ispreferably used for internal calibration of the system and for testingand calibration of the probes.

For internal testing and calibration, calibration reference 232 receivesthe signals generated by the programmable reference signals generator aspassed to the selection switch, in series with an internal admittance inthe calibration reference, as selected by the DSP processor. The DSPprocessor computes the admittance from signals received from the A/Dconvertor and compares the computed admittance with the actualadmittance provided by internal calibration reference 332. Thiscomparison can be provide an indication that the system requiresadjustment or repair or can be used to calibrate the system.

Similarly, the output of calibration reference 332 may be provided toprobe cover 88 for calibration and quality assurance of a plate or scanprobe as described above. Under this situation, the DSP instructsselection switch 304 to choose the input from the respective probe.

Also provided is a user interface 334 such as a keyboard, mouse,joystick or combinations thereof, to allow the operator to enterpositional information via the screen and to choose from among theprobes provided and from the many options of calculation, display, etc.

Although described together as the preferred embodiment of theinvention, it is not necessary to use the probes of the invention, themethods of calculation of impedance and impedance characteristics of theinvention and the preferred apparatus of the invention together. Whileit is presently preferred that they be used together they may each beused with probes, calculation methods and apparatus for impedanceimaging as applicable and as available.

Certain aspects of the invention have been described with respect to abiopsy needle or with respect to placement of such a needle. It shouldbe understood that such description and aspects of the invention areequally applicable to positioning needles, catheters, endoscopes, etc.

Although various embodiments, forms and modifications have been shown,described and illustrated above in some detail in accordance with theinvention, it will be understood that the descriptions and illustrationsare by way of example, and that the invention is not limited thereto butencompasses all variations, combinations and alternatives falling withinthe scope of the claims which follow:

1. A method of electrical impedance testing of a breast region of apatient, comprising: applying electrical excitation signals to thepatient; acquiring electrical signals from the breast region of thepatient, through a plurality of elements of a multi-element probeincluding at least two rows and two columns of sensing elements,responsive to the applied signals; and determining a single value of animpedance measure of the breast region, responsive to the signalsacquired through more than one of the plurality of elements of theprobe.
 2. A method according to claim 1, comprising displaying thedetermined value of the impedance measure to a user.
 3. A methodaccording to claim 1, wherein signals are acquired through elements ofthe probe placed on the region and elements of the probe not on theregion and wherein the value of the impedance measure is determinedbased only on signals from elements placed on the region.
 4. A methodaccording to claim 1, wherein the value of the impedance measure isdetermined based only on signals from elements whose values lie within aspecified range.
 5. A method according to claim 1, wherein determiningthe single value comprises selecting a sub-group of elements anddetermining the value based on the selected elements.
 6. A methodaccording to claim 5, wherein selecting the sub-group of elementscomprises selecting based on the signals acquired through the elements.7. A method according to claim 5, wherein selecting the sub-group ofelements comprises selecting an area of an impedance image.
 8. A methodaccording to claim 5, wherein the value of the impedance measure isdetermined based only on signals from elements whose values are notamong the highest or lowest values of all the elements.
 9. A methodaccording to claim 5, wherein the value of the impedance measure isdetermined based only on signals from elements whose values are notindicative of contact problems.
 10. A method according to claim 1,wherein the region for which the value of the impedance measure isdetermined comprises a region chosen by a user.
 11. A method accordingto claim 1, comprising comparing the single value of the impedancemeasure of the breast region to a value of a reference region.
 12. Amethod according to claim 1, wherein values of the impedance measure aredetermined separately for each of the plurality of the probe elementsused in determining the single value, and wherein the single impedancemeasure is determined as a function of the impedance measure of theplurality of elements.
 13. A method according to claim 12, wherein thesingle impedance measure far the region is determined as a maximum ofthe impedance measure of the plurality of elements.
 14. A methodaccording to claim 1, wherein acquiring the electrical signals comprisesacquiring through a flat multi-element probe in which substantially allthe elements are oriented in a same direction.
 15. A method according toclaim 1, wherein the impedance measure comprises a phase.
 16. A methodaccording to claim 1, wherein the impedance measure comprises apolychromatic measure.
 17. A method according to claim 1, whereinacquiring the electrical signals comprises acquiring through amulti-element probe including at least 16 elements.
 18. A method ofelectrical impedance testing of a breast region of a patient,comprising: applying electrical excitation signals to the patient;acquiring electrical signals from the breast region of the patient,through a plurality of elements of a multi-element probe, responsive tothe applied signals; generating an impedance map of the regionresponsive to the acquired signals and determining a single value of animpedance measure of the breast region for a region of pixels of theimpedance map, responsive to the acquired signals.
 19. A methodaccording to claim 18, wherein acquiring the electrical signalscomprises acquiring through a multi-element probe including arectangular matrix of elements, including at least two columns and tworows.
 20. Apparatus for electrical impedance testing of a breast regionof a patient, comprising: an electrode for providing electrical signalsto the patient; a multi-element probe, including at least 16 elements,for acquiring electrical signals from the patient, through a pluralityof elements, responsive to the provided signals; and a processor adaptedto determine a single value of an impedance measure of the breastregion, responsive to signals acquired through more than one of theplurality of elements of the probe from the region.
 21. Apparatusaccording to claim 20, comprising a display for providing the determinedvalue of the impedance measure, to a user.
 22. Apparatus according toclaim 20, comprising a controller adapted to acquire signals throughelements of the probe placed on the region and elements of the probe noton the region and wherein the processor determines the value of theimpedance measure based only on signals from elements placed on theregion.
 23. Apparatus according to claim 20, comprising an inputinterface adapted to receive a user indication of the region for whichthe value of the impedance measure is determined.
 24. Apparatusaccording to claim 20, wherein the processor is adapted to generate animpedance map of the region responsive to the acquired signals and todetermine the single value of the impedance measure for a region ofpixels of the impedance map.
 25. Apparatus according to claim 20,wherein the processor is adapted to compare the single value of theimpedance measure of the breast region to a value of a reference region.26. Apparatus according to claim 20, wherein the processor is adapted todetermine values of the impedance measure separately for each of theplurality of the probe elements used in determining the single value,and to determine the single impedance measure as a function of theimpedance measure of the plurality of elements.
 27. Apparatus accordingto claim 26, wherein the processor is adapted to determine the singleimpedance measure for the region as a maximum of the impedance measureof the plurality of elements.
 28. Apparatus according to claim 20,wherein the probe comprises a flat multi-element probe in whichsubstantially all the elements are oriented in a same direction. 29.Apparatus according to claim 2, wherein the probe comprises amulti-element probe including a rectangular matrix of elements.